A wide range of disorders involves the hyperproliferation of cells, ranging from psoriasis to benign and malignant tumors. These disorders are generally caused by a loss of control over normal cell growth, differentiation, or the process of programmed cell death (apoptosis). Many of the abnormalities that underlie these disorders, particularly cancer, occur at the genetic level. Antineoplastic agents (also known as cytotoxic agents) are often used in the treatment of hyperproliferative conditions. Therapy with antineoplastic agents is successful in the treatment of a number of malignant conditions; however, in most it is used to palliate the symptoms and to prolong life in patients with advanced disease. Two groups of drugs used in the treatment of hyperproliferative conditions are antimetabolites and alkylating agents. Antimetabolites can be subdivided into folic acid, purine and pyrimidine derivatives. In addition, several natural products, or their derivatives, have been used as mitotic inhibitors. These include vinca alkaloids, and the derivatives of podophyllotoxin. There remains an effort in the research community to understand the genetic basis for abnormal cell hyperproliferation, which can vary among its various manifestations, and to develop therapeutic methods to successfully treat these serious conditions.
For about four decades, the antimetabolite 5-fluorouracil (5-FU), and nucleosides that include this base (e.g., 5-fluoro-2′-deoxyuridine or FdUrd), have remained among the few “standard” drugs effective against solid tumors in man. 5-Fluorouracil is used mainly for the treatment of colorectal, ovarian, renal, breast and head and neck cancers. 5-Fluoro-2′-deoxyuridine is used for the treatment of solid tumors, including hepatic metastases of advanced gastrointestinal adenocarcinomas, renal cell carcinomas, advanced ovarian cancer, and squamous cell carcinomas of the head and neck. The clinical utility of the fluoropyrimidines is limited by the host-toxicity induced by the administration of these compounds. Manifestations of the host-toxicity of the fluoropyrimidines include mainly gastrointestinal epithelial ulceration, myelosuppression and, to a lesser extent, cardiotoxicities, hepatotoxicities and neurotoxicities.
A population of cancer patients is intolerant to treatment with 5-fluorouracil and 5-fluoro-2′-deoxyuridine. The intolerance to 5-fluorouracil was initially attributed to a deficiency or low activity of dihydrouracil dehydrogenase (DHUDase, EC 1.3.1.2), the first enzyme in the catabolic pathway of 5-fluorouracil. However, it appeared that not all intolerant patients showed reduced dihydrouracil dehydrogenase activities. Moreover, it has also been shown that cancers, treated with fluoropyrimidines, become resistant, i.e., develop tolerance towards these drugs.
Colorectal cancer (CRC) is a multi-step process resulting from the accumulation of mutations in clonal populations of colonocytes. Mutations of the p53 tumor suppressor gene are a relatively late, yet common event in the pathogenesis of colorectal cancer, occurring in over 80% of late adenomas and carcinomas (Fearon, et al., FASEB J. 6, 2789 (1992); Srivastarva, et al., Contemp. Oncol. April 63 (192); Kline, et al., Cancer (Phila. 73, 28 (1994). Conventional therapy for advanced disease, such as cytotoxic chemotherapy and gamma-irradiation, induce DNA damage in proliferating cells. This damage, through undefined mechanism(s), signals the induction of p53, which, in turn, leads to inhibition of cellular proliferation by induction of G1 cell cycle arrest and, in some instances, apoptosis. Thus, tumors lacking functional p53 are frequently refractory to such therapies (S. C. Righetti et al., Cancer Res. 56, 689 (1996); J. S. Kovack et al., Proc. Natl. Acad, Sci. U.S.A. 93, 1093 (1996)), emphasizing the importance of developing treatments for advanced colorectal cancer that do not rely on functional p53.
The most effective single chemotherapeutic agent for advanced colorectal cancer to date remains 5-FU. The active metabolite of 5-FU, 5-fluorodeoxyuridine-5′-monophosphate (FdUMP), forms a complex with thymidylate synthase (TS) in the presence of reduced folate, thereby inhibiting enzyme activity, and depleting precursors for DNA synthesis. 5-FU is also incorporated into RNA, altering its processing and function, although how this correlates with cytotoxicity is unknown. Previous data suggest that 5-FU can utilize both p53-dependent and independent pathways (Pritchard, et al., Pharmacol Ther. 72, 149 (1996)), although a loss of p53 function dramatically reduces 5-FU efficacy (B. Cohen et al., Cancer (Phila.) 67, 1859 (1991); Advanced Cancer Meta-Analysis Project, J. Clin. Oncol. 10, 896 (1992)).
In view of the lack of successful treatments for many hyperproliferative conditions, it would be of benefit both to identify important biological pathways that mediate the loss of normal cell function, including programmed cell death (i.e., apoptosis), and to identify compositions and methods for the treatment of these disorders.
U.S. Pat. Nos. 5,035,878 and 5,294,430 disclose that dithiocarbamates can reverse the damage to the blood-forming function of the bone marrow (myelosuppression) caused by treatment with antineoplastic agents.
It is therefore an object of the invention to provide a method and composition for the treatment of abnormal cell proliferative conditions, including benign and malignant tumors.
It is another object of the present invention to provide a method and composition for the treatment of colon cancer.
It is a further object of the present invention to provide a method and composition for the treatment of solid tumors.
It is yet another object of the present invention to provide a method and composition for the treatment of diffuse tumors.